We tested a panel of ten different natural products and identified the aqueous extract from Sargassum fusiforme (S. fusiforme) as a highly efficient inhibitor of HIV-1 replication in T cells and macrophages, the two main cell types of viral infection. S. fusiforme inhibits viral infection and replication by over 90%, which is comparable to treatment with the nucleoside analogue 2', 3'- didoxycytidine (ddC). The observed HIV-1 inhibition is at the level of virus fusion and direct inhibition of reverse transcriptase (RT), is long lasting, does not inhibit cell growth, is not toxic to cells, and inhibits syncytium formation and spread of HIV-1 infection to uninfected cells. We hypothesize that aqueous extract derived from S. fusiforme contains certain novel biologically active molecules such as sulfated polysaccharides, algal polyphenols or other small molecules that act in concert via distinct mechanisms to restrict HIV-1 infection and replication. We will test this hypothesis with the following Specific Aims: 1) to conduct a bioactivity guided, comprehensive fractionation of the whole aqueous extract derived from S. fusiforme, and to isolate, identify, and test biologically active compounds responsible for the inhibition of HIV-1 replication, and 2) to identify specific molecular mechanisms of action by which the whole S. fusiforme botanical inhibits the HIV-1 life cycle and contributes to the shift from productive to restricted HIV-1 infection. Our long-term objectives are to develop new strategies aimed at preventing HIV-1 infection and replication by natural products.